8-132888417-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003235.5(TG):c.2610G>T(p.Gln870His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,570 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (34 hom.)
• Consequence: TG NM_003235.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.64

Genes affected

TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05794525).
• BP6: Variant 8-132888417-G-T is Benign according to our data. Variant chr8-132888417-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12690.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TG	NM_003235.5	c.2610G>T	p.Gln870His	missense_variant	10/48	ENST00000220616.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TG	ENST00000220616.9	c.2610G>T	p.Gln870His	missense_variant	10/48	1	NM_003235.5	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 454 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00461

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00306 AC: 768 AN: 251104 Hom.: 3 AF XY: 0.00333 AC XY: 452 AN XY: 135704

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00334

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00469 AC: 6848 AN: 1461258 Hom.: 34 Cov.: 38 AF XY: 0.00467 AC XY: 3396 AN XY: 726802

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00349

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.00547

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00298 AC: 454 AN: 152312 Hom.: 1 Cov.: 32 AF XY: 0.00258 AC XY: 192 AN XY: 74470

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00336 Hom.: 0

Bravo AF: 0.00281

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00421

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Iodotyrosyl coupling defect Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 01, 2005	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Premature ovarian failure Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Apr 22, 2019

This variant was identified as homozygous in a female individual with hypergonadotropic hypogonadism. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.63		Gain of catalytic residue at L872 (P = 0.0918);
MVP		0.82
MPC		0.34
ClinPred		0.030	T
GERP RS		3.1
Varity_R		0.22
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229843; hg19: chr8-133900662; COSMIC: COSV105016342;